Objective To investigate the metabolic changes in the visual cortex due to visual stimulation using high field functional proton magnetic resonance spectroscopy at 7.0 T.A clear picture of brain metabolism and neurotransmitter activity during activation was expected to be established.Methods Nine healthy subjects participated in this study. All MR measurements were acquired using a 7.0 T MR system and a 16-channel SENSE head coil. An initial fMRI scan was performed prior to spectroscopic acquisition in order to determine the activated region in the visual cortex.A cubic ROI of 2 cm× 2 cm × 2 cm was positioned inside the activated region for functional MRS acquisition.A short TE STEAM sequence was used for acquiring the MRS data. The functional paradigm comprised 6.6 min baseline followed by 13.2 min of visual stimulation and 19.8 min recovery.Summed averaged spectra for visual stimulus off and visual stimulus on were analyzed separately using LC Model and internal reference of water. A Wilcoxon signed rank test was conducted to compare the metabolite changes. ResultsDuring stimulation,concentration in Asp [ ( 3.20 ± 0.28 ) μmol/g ],Gln [ ( 2.07 ± 0.10 ) μmol/g ] and Gly [ ( 1.65 ± 0.11 )μmol/g ] was found to be significantly decreased,compared with that of ( 3.52 ± 0.28 ),( 2.25 ± 0.10 ) and ( 1.85 ± 0.11 ) μmol/g in rest ( Z =- 2.073,- 2.073 and - 2.429,respectively,P ＜ 0.05 ).The level in Glu [ ( 11.50 ± 0.11 ) μmol/g],GSH[ (2.45 ± 0.10) μmol/g] and Lac[ (0.89 ± 0.05) μ.mol/g]due to neuronal activation was found to be significantly increased,versus resting concentration of ( 11.28 ± 0.11 ),( 2.28 ± 0.10 ) and (0.79 ± 0.05 ) μmol/g,respectively ( Z =2.521,2.310,2.016,respectively,P ＜0.05).Glc level [ (1.54 ± 0.23 )μmol/g] exhibited a tendency to decrease throughout the period of stimulation,compared with that of [ (1.78 ± 0.28 ) μmol/g ] in rest,but the decrease did not reach statistical significance (Z =- 1.897,P ＞ 0.05 ).ConclusionsUsing a novel visual stimulation paradigm and 1 H MRS at 7.0 T and LC Model,the metabolic response to activation have been able to be observed.The observed changes of Asp,Glc and Lac concentrations in response to visual stimulation suggests that sustained neuronal activation raises oxidative metabolism to a new steady state.The observation of increased Glu with decreased Gln during stimulation can be interpreted as a stimulus driven increase in excitatory neurotransmitter cycling.The elevated GSH in the visual cortex in response to visual stimulation is a new observation.Possible explanations for this include detoxification of reactive oxygen species.

OBJECTIVE TNF- related apoptosis- inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors. However, most breast cancer cells are resistant to TRAIL- induced apoptosis. Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance. METHODS To identify modulators of TRAIL-induced apoptosis, we carried out a genome wide siRNA screen. To validate the screening result, we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model. Finally, we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy. RESULTS We unexpectedly identified androgen receptor (AR) to be responsible for TRAIL resistance. While AR is classically viewed as the key factor in prostate cancer progression, we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple- negative breast cancers (TNBC) that are highly aggressive with poor prognosis. Importantly, breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance. AR overexpression in MDA- MB- 231 and MDA- MB- 436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis. AR overexpression also induced TRAIL resistance in breast tumors in vivo. Further, we observed an upregulation of the TRAIL receptor, death receptor 5 (DR5) in breast cancer cells, following the removal or inhibition of AR by its antagonists Casodex and MDV3100. Treatment with AR antagonists also enhanced TRAIL- induced breast cancer cell apoptosis. CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis, in part, by suppressing DR5 expression, and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.

Objective To evaluate whether the number of high intensity transient signals(HITS)intraoperative detected by transcranial doppler ultrasound(TCD)can predict postoperative neuropsychological deficit.Methods Twenty patients scheduled for coronary artery bypass grafting(CABG)operation with cardiopulmonary bypass were enrolled in this study.HITS were recorded by TCD intraoperatively.And neuropsychological test battery was used to assess postoperative neuropsychological changes.Results There was no significant difference in the number of HITS compared with patients with or without neuropsychological changes.And multivariable correlation between the test scores and the number of HITS showed there was a weak correlation between RW Dgt-Dg5 and HITS(P＜0.05).Conclusion The number of HITS detected during cardiopulmonary bypass(CPB) do not!correlate with the postoperative neuropsychologial changes.

Intravenous thrombolysis is an effective treatment for acute ischaemic stroke. However, vascular recanalization rates remain poor especially in the setting of large artery occlusion. On the other hand, endovascular intra-arterial therapy addresses this issue with superior recanalization rates compared with intravenous thrombolysis. Although previous randomized controlled studies of intra-arterial therapy failed to demonstrate superiority, the failings may be attributed to a combination of inferior intra-arterial devices and suboptimal selection criteria. The recent results of several randomized controlled trials have demonstrated significantly improved outcomes, underpinning the advantage of newer intra-arterial devices and superior recanalization rates, leading to renewed interest in establishing intra-arterial therapy as the gold standard for acute ischaemic stroke. The aim of this review is to outline the history and development of different intra-arterial devices and future directions in research.
Arteries ; Hand ; Patient Selection ; Stroke*

The first author's name was misprinted.

Pharmacogenomics (or pharmacogenetics), the study of the effects of genetic differences on a person’s response to drugs, can help in optimizing drug efficacy and minimizing adverse drug reactions. Interperson difference in drug metabolism is one of the important consequences of such genetic variation. This variation is determined in part by mutations in cytochrome P450 enzymes (CYPs). IMU is part of a major collaborative research project in the area of phamacogenetics and drug metabolism. Working together with USM and UiTM, our group has, since 2000, generated useful population database on genetic polymorphism of various CYP isoforms. We have successfully genotyped three major ethnic groups, Malay, Indian and Chinese for their allelic frequency of important isoforms. These include CYP2D6, CYP2C9, CYP2C8 and CYP2A6. Data generated so far collectively have contributed to our effort in mapping and constructing genomic database for Malaysian population. Since early 2002, our research has been focusing on developing in vitro methods in studying the functional consequences of genetic polymorphism of CYP enzymes. Using site-directed mutagenesis, CYP mutants, carrying nucleotide changes as reported in known alleles in human populations, were generated and expressed in E. coli system, and the expressed recombinant proteins were characterized using enzyme assays to determine the functional consequences of mutations. We have established a series of HPLC (high performance liquid chromatography)-based and fluorescence-based assays to investigate CYP activities. Assays that have been developed include tolbutamide methylhydroxylase, paclitaxel 6a-hydroxylase, dextromethorphan O-demethylation, testosterone 6b-hydroxylation and coumarin 7-hydroxylase assays. These assays serve as activity markers allowing comparison of catalytic activities of mutant proteins generated. Another focus of our work is to use the developed assays as a screening tool to investigate drug-herb interactions. This was achieved by co-incubation of herbal extracts and active constituents with the probe substrates in the assays followed by characterization of the kinetic behaviors of the enzymes involved using various pharmacokinetic parameters such as Km, Vmax, IC50 and Ki. This work is currently carried out with collaboration from the Institute for Medical Research (IMR) and is supported by MOSTI’s eScienceFund under RM9. It is envisaged that this screening work will give us insights on the potential of the commonly used herbs to cause pharmacokinetic interactions with other drug substrates, and allow us to elucidate the mechanisms involved in the interactions.

OBJECTIVETo investigate the pretreatment effects of Rhodiola rosea (R. rosea) extract on cognitive dysfunction, oxidative stress in hippocampus and hippocampal neuron injury in a rat model of Alzheimer's disease (AD).

METHODSMale Sprague-Dawley rats were pretreated with R. rosea extract at doses of 1.5, 3.0, and 6.0 g/kg for 3 weeks, followed by bilateral intracerebroventricular injection with streptozotocin (1.5 mg/kg) on days 1 and 3. Behavioral alterations were monitored after 2 weeks from the lesion using Morris water maze task. Three weeks after the lesion, the rats were sacrificed for measuring the malondialdehyde (MDA), glutathione reductase (GR) and reduced glutathione (GSH) levels in hippocampus and histopathology of hippocampal neurons.

RESULTSThe MDA level was significantly increased while the GR and GSH levels were significantly decreased with striking impairments in spatial learning and memory and severe damage to hippocampal neurons in the model rat induced by intracerebroventricular injection of streptozotocin. These abnormalities were significantly improved by pretreatment with R. rosea extract (3.0 g/kg).

CONCLUSIONR. rosea extract can protect rats against cognitive deficits, neuronal injury and oxidative stress induced by intracerebroventricular injection of streptozotocin, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD.

Animals ; Behavior, Animal ; drug effects ; Biomarkers ; metabolism ; Cell Count ; Cognition Disorders ; chemically induced ; drug therapy ; physiopathology ; Hippocampus ; drug effects ; pathology ; Injections, Intraventricular ; Male ; Neurons ; drug effects ; pathology ; Neuroprotective Agents ; pharmacology ; Oxidative Stress ; drug effects ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Rhodiola ; metabolism ; Streptozocin ; administration & dosage ; Swimming ; physiology

Endovascular neurointervention is typically performed with iodinated contrast medium (ICM) under fluoroscopy. However, some patients may be contraindicated to such procedures based on their sensitivity to ICM. In this report, we describe a case of successful coil embolization of a direct carotid cavernous fistula using angiography with gadolinium-based contrast agents in a patient with severe allergic reaction to ICM. The clinical decision-making for this patient was further complicated by comorbidities of renal impairment, drug allergies, and previously severe gastrointestinal bleeding.

BACKGROUND AND PURPOSE: Leptomeningeal collaterals maintain arterial perfusion in acute arterial occlusion but may fluctuate subject to arterial blood pressure (ABP). We aim to investigate the relationship between ABP and collaterals as assessed by computer tomography (CT) perfusion in acute ischemic stroke. METHODS: We retrospectively analyzed acute anterior circulation ischemic stroke patients with CT perfusion from 2009 to 2014. Collateral status using relative filling time delay (rFTD) determined by time delay of collateral-derived contrast opacification within the Sylvian fissure, from 0 seconds to unlimited count. The data were analyzed by zero-inflated negative binomial regression model including an appropriate interaction examining in the model in terms of occlusion location and onset-to-CT time (OCT). RESULTS: Two hundred and seventy patients were included. We found that increment of 10 mm Hg in BP, the odds that a patient would have rFTD equal to 0 seconds increased by 27.9% in systolic BP (SBP) (p=0.001), by 73.9% in diastolic BP (DBP) (p<0.001) and by 68.5% in mean BP (MBP) (p<0.001). For patients with rFTD not necessarily equal to 0 seconds, every 10 mm Hg increase in BP, there was a 7% decrease in expected count of seconds for rFTD in SBP (p=0.002), 10% decrease for rFTD in DBP and 11% decrease for rFTD in MBP. The arterial occlusion location and OCT showed no significant interaction in the BP-rFTD relationship (p>0.05). CONCLUSIONS: In acute ischemic stroke, higher ABP is possibly associated with improved leptomeningeal collaterals as identified by decreased rFTD.
Arterial Pressure ; Blood Pressure* ; Humans ; Perfusion ; Reperfusion* ; Retrospective Studies ; Stroke*

To validate the use of the Index of Complexity, Outcome and Need (ICON) in assessing orthodontic treatment need among 12-13 year-olds in southern China, we determined the threshold value of ICON based on Chinese orthodontists' judgments. The samples consisted of 335 students in grade 7 from 16 randomly selected middle schools in Chengdu, China. Three associate professors provided ICON scores for each participant and the results were compared with the gold standard judgments from 25 experts on treatment needs. Based on the gold standard, 195 casts belonged to the treatment category, while the rest 140 belonged to the no-treatment category. With the international cutoff point of 43, the sensitivity and specificity of the ICON score were 0.29 and 0.98.The best compromise between sensitivity and specificity in Chengdu, compared with the gold standard, was found at a cutoff point of 29, and the sensitivity and specificity were 0.88 and 0.83. When used to evaluate the treatment need of 12-13 year-olds in southern China, the international ICON cutoff value did not correspond well with Chinese orthodontists' judgments; a lower cutoff value of 29 offered a greater sensitivity and specificity with respect to expert orthodontists' perception of treatment need.
Adolescent ; Child ; China ; epidemiology ; Cross-Cultural Comparison ; Data Collection ; Dental Health Surveys ; methods ; standards ; Female ; Health Services Needs and Demand ; statistics & numerical data ; Humans ; Male ; Malocclusion ; diagnosis ; epidemiology ; Needs Assessment ; statistics & numerical data ; Observer Variation ; Orthodontics, Corrective ; standards ; statistics & numerical data ; Reference Values ; Reproducibility of Results ; Sensitivity and Specificity